Despite major public health efforts, tuberculosis (TB) is now the most common infectious disease cause of death worldwide. Tuberculosis infection is a respiratory infection in which the bacteria and immune response are localized within a lung granuloma, an aggregate of immune cells (T cells, neutrophils, B cells and macrophages) that functions to immunologically contain the bacteria. A thorough understanding of the immune response to infection is desperately needed to develop an effective and preventive vaccine against TB. In this proposal, we will focus on understanding the role of CD8 during infection as these cells have been largely understudied, especially within the granuloma. We will first directly address whether CD8 T cell are necessary to control early infection with Mycobacterium tuberculosis. Using a non-human primate model of human infection, we will compare disease progression by modern imaging methods during the course of infection. We will also map bacterial spread using sophisticated molecular techniques. Our second objective will be to characterize the types of CD8 cells in the granuloma and their specific immunologic function against M. tuberculosis. Lastly, we will examine how the CD8 cells influence functional pathways of other immune cells in the granuloma using novel single cell methods. Results of these studies will not only provide a more thorough understanding of the role of CD8 T cells in the immune response to M. tuberculosis but are likely to lead to improved vaccine strategies, especially as they apply to patient with HIV-TB co-infection.